Síntesis de nuevas isoquinoleínas 1-sustituidas con actividad antibacteriana y antifúngica o dopaminérgica
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2015
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19-02-2016
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Cortés Martínez, Diego M.
Sanz Ferrando, María Jesús
Cabedo Escrig, Nuria
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Abstract
Nature has provided for decades a huge number of active secondary metabolites (ASM) with a broad spectrum of therapeutic applications. For decades, our research group has focused its studies on the isolation of active secondary metabolites from plants belonging to the Annonaceous family and on the development of structural analogues of some ASM such as acetogenins and isoquinoline alkaloids, which may be biologically active.
Therefore, in the present Doctoral Thesis we proposed the achievement of the following objectives:
1- Study of the different types of ASM present in the Annonaceous family that may inspire the development of new drugs with particular emphasis findings encountered by our group in the last decades.
2- Synthesis and determination of the antibacterial and antifungal activity of:
a) 1-Alkyl-tetrahydroisoquinolines functionalized with carbamates and esters.
b) Pirrolo[2,1-a]isoquinolin-3-ones.
3- Synthesis of hexahydrocyclopentylisoquinolines and study of their affinity towards type-D1 and type-D2 dopaminergic receptors.
In Chapter I a brief study regarding the different ASM present in plants from the Annonaceous family has been done. It has been mainly described the findings encountered by our group on mitochondrial respiratory chain (MRC) inhibition by acetogenins such as laherradurin, the semisynthetic 15,24-diacetylguanacone, squamocin and its different semisynthetic derivatives.
In Chapter II the synthesis of 1-substituted tetrahydroisoquinolines (THIQ) with antibacterial and antifungal or dopaminergic activity is described.
In the first section we review the bibliographic backgrounds of both, chemical synthesis and biological activities that led us to carry out the study.
In the second section of this chapter, we present the synthesis of THIQ with antibacterial and antifungal activity. First it is develop the synthesis of 1-substituted THIQ functionalized with an ester or carbamate. The synthesis of the isoquinoline core is performed by a Bischler-Napieralski cyclodehydration from the β-phenylethylamide. Next, by means of an N-methylation, subsequent reduction of the imonium and a modification of the terminal ester at the alkyl chain, the 1-pentanol-THIQ 2c is obtained. From this compound derivatives with ester 2d-2k or carbamate 2l-2s function substituted with different phenyls or phenethyls have been synthesized. Next, it is shown the synthesis of pyrrolo[2,1-a]isoquinolin-3-ones carried out. A β-phenylethylamide with a terminal ester at a shorter alkyl chain allows a double cyclization leading to this type of THIQ. Pyrrolo[2,1-a]isoquinolin-3-ones with different substituents at 8-position were then synthesized.
The evaluation of the antibacterial and antifungal activity of the synthesized THIQ were carried out by the paper disk-agar diffusion method measuring the inhibition halos. Regarding the antibacterial activity of the 1-alkyl-THIQ, all compounds functionalized with an ester 2d-2k or carbamate 2l-2s displayed activity against the tested bacteria. Among the 1-pentyl-THIQ with ester function 2d-2k, we observed that, in general terms, the most active compounds have a fluorinated substituent at the aromatic ring (2e and 2i). It should be noted that the 1-pentyl-THIQ with carbamate function and with a fluorinated (2m and 2q) or chlorinated (2n and 2r) aromatic ring showed also greater antibacterial activity.
In regard to the antifungal activity of 1-alkyl-THIQ, the relevance of introducing lipophilic substituents through an ester or carbamate function to achieve active products against the assayed fungi has been observed. In general, the 1-pentyl-THIQ with ester function 2d-2k showed greater activity than the derivatives functionalized with a carbamate 2l-2s. Among the THIQ with ester function, it was noteworthy the effect displayed by the compounds with chlorinated substituents 2f and 2j.
The pyrrolo[2,1-a]isoquinolin-3-ones substituted at 8-position with a lipophilic group, were found to be active against most of the tested bacteria. Notably products 3a and 3d displayed antifungal activity against all fungi assayed.
In the third section of the second chapter the procedure used to synthesize 7-phenyl-hexahydrocyclopentylisoquinolines (HCPIQ) using Eaton’s reagent has been described. N-alkylated HCPIQ with methoxylated or deprotected hydroxyls groups have been synthesized.
The affinity study towards type-D1 and type-D2 dopaminergic receptors was carried out in vitro by a competition assay with radioligands on rat striatal membranes.
All HCPIQ have shown affinity towards type-D1 and type-D2 DR at a micromolar or nanomolar range. In general, catecholic compounds displayed greater affinity than their dimethoxylated analogues. In catecholic HCPIQ we observed a significant increase of the affinity towards type-D1 DR by introducing a methyl or allyl substituent at the nitrogen. It should be noted the great affinity and selectivity towards type-D2 DR revealed by the catecholic HCPIQ 4b, 4d and 4f. Compound 4b showed a Ki value of 29 nM and a Ki D1/D2 ratio of 2465. The N-methylated product 4d displayed a high affinity (Ki = 13 nM) and a selectivity ratio Ki D1/D2 of 1010. The N-allyl-HCPIQ 4f showed a Ki value of 18 nM and a Ki D1/D2 ratio of 382.
Regarding these results we achieved the following conclusions:
1. The active secondary metabolites from plants of the Annonaceous family, mainly acetogenins and isoquinoline alkaloids, have inspired our research group for decades leading to the development of new compounds with biological activity.
2. Of note, all THIQ with an ester or carbamate function substituted with different phenyls or phenethyls, showed antibacterial activity against all the species tested, highlighting compounds bearing halogenated substituents. In regard to the antifungal activity, compounds with an ester function showed generally greater activity than the THIQ with a carbamate function.
3. Pyrrolo[2,1-a]isoquinolin-3-ones with a lipophilic substituent at 8-position showed antibacterial activity against most of the bacteria tested. Notably, benzylated products exerted antifungal activity against all fungal species assayed.
4. The catecholic hexahydrocyclopentylisoquinolines showed remarkable high affinity (nanomolar range) and relevant selectivity towards type-D2 dopaminergic receptors.